There are 16,000 new cases of HIV infection everyday with over 36.1 million people living with HIV/AIDS today. Worldwide, the vast majority of new infections with HIV are acquired through sexual transmission, the major route of transmission to the 16.4 million infected women. Compounds that are developed for topical use to prevent HIV transmission (microbicides) offer a promising and perhaps more easily realized alternative to development of an effective vaccine. However, recent disappointing experience with a widely used contraceptive, nonoxynol-9, emphasizes the need for extensive preclinical evaluation of compounds for antiviral efficacy and toxicity prior to their widespread use as a topical microbicide. This Program Project Grant will focus on the development of a novel class of candidate compounds based on the parent compound, sodium dimandelic acid ether (SAMMA). SAMMA has antiviral activity against laboratory-adapted and primary isolates of HIVas well as herpes simplex virus (HSV), the sexually transmitted disease that is a major cofactor for HIV, without apparent cytotoxicity. It inhibits sperm function and prevents fertilization in the rabbit. Through the rational design of compound derivatives synthesized by a core laboratory, critical structure/function relationships will be determined for this class of compounds in studies designed to define the full HIV (Projects 1 and 3) and HSV (Projects 2 and 3) inhibitory spectrum, cytotoxicity (Projects 1,2,3 and 4), mechanism(s) of inhibition (Projects 1 and 2) and contraceptive potential (Project 4). Mechanism studies will extend preliminary observations that the parent compound works at an early step in viral entry for both HIV and HSV by carefully studying viral and viral glycoprotein interactions with cell membrane ligands involved in attachment and entry (Projects 1 and 2). Initial cell interactions will be examined by using primary epithelial cells, T -cells, macrophages and dendritic cells. To more closely simulate the anatomical, physiologic and immunological environment of the genital mucosa, Project 3 will examine the efficacy in cervical lavage and seminal fluid as well as efficacy in human mucosal explant cultures and in a murine model of HSV. Lastly, through co-culture of HIV and HSV in primary cells and in the cervical mucosal explant culture, the added benefit of targeting both viruses with topical microbicides will be defined. The proposed comprehensive evaluation of this class of compounds will determine if it should progress to clinical evaluation.